Chiral Aryliodine-Mediated Enantioselective Organocatalytic. Spirocyclization: Synthesis of Spirofurooxindoles via Cascade

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1 Chiral Aryliodine-Mediated Enantioselective Organocatalytic Spirocyclization: Synthesis of Spirofurooxindoles via Cascade Oxidative C O and C C Bond Formation Yang Cao, Xiang Zhang, Guangyu Lin, Daisy Zhang-Negrerie, and Yunfei Du*,, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin , China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin , P. R. China duyunfeier@tju.edu.cn Supporting Information I. General Information S2 Page II. Mechanistic Studies III. Preparation of Substrate 1 IV. Preparation of the Optically Inactive Spirofurooxindoles 2 S2 S3 S4 S5 S5 S6 V. Preparation of Chiral Iodobenzene 3 S6 S7 VI. Preparation of the Optically Active Spirofurooxindoles 2 VII. References VIII. 1 H-NMR, 13 C-NMR Spectra and HPLC Data IX. X-ray Structure and Data of 2a and (R)-2b S7 S30 S31 S32 S147 S148 S166 S1

2 I. General Information All reactions were carried out at room temperature under air unless otherwise stated. 1 H and 13 C NMR spectra were recorded on 600 MHz or 400 MHz spectrometer at 25 o C. Chemical shifts values are given in ppm and referred as the internal standard to TMS: 0.00 ppm. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; m, multiplet and dd, doublet of doublets, brs, broad singlet. The coupling constants J, are reported in Hertz (Hz). High resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectrometer. Melting points were determined with a Micromelting point apparatus without corrections. Infrared spectra were measured on a FT/IR instrument. HPLC analysis was conducted using Ultimate 3000 and chiral column of Daicel CHIRALCEL AD-H (4.6 mm 25 cm), OJ-H (4.6 mm 25 cm) and OD-H (4.6 mm 25 cm). Organic solutions were concentrated by rotary evaporation below 40 C in vacuum. TLC plates were visualized by exposure to ultraviolet light. Reagents and solvents were purchased as reagent grade and were used without further purification. All reactions were performed in standard glassware, heated at 70 o C for 3 h before use. Flash column chromatography was performed over silica gel m and the eluent was a mixture of ethyl acetate (EA) and petroleum ether (PE). II. Mechanistic Studies S2

3 a. Preparation of intermediate A To a solution of substrate 1p (1.0 mmol) in TFE (10 ml) was slowly added PIFA (1.0 equiv) with stirring. The resulting mixture was maintained at room temperature, and the process of the reaction was monitored by TLC. Upon completion, the reaction solvent was removed under vacuum and the residue was purified by silica gel chromatography, using a mixture of PE/EA (30% EA/PE) to afford the intermediate A (89%, 257mg). b. Preparation of the optically active spirofurooxindoles 2p To a reaction tube filled with the intermediate A (0.2 mmol), chiral organoiodine 3d (10 mol%), mcpba (1.3 equiv) and TFE/CH 3 CN (4.0 ml) was added CF 3 CO 2 H (4.0 equiv). The resulting mixture was allowed to be stirred at room temperature for 8 h. The mixture was filtered, washed with CH 3 CN (2 ml 2), the combined organic phase was removed in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/etoac = 3/1) to afford optically active spirofurooxindoles 2p as a white solid (75%, 43 mg). c. Preparation of the optically active intermediate A To a reaction tube filled with substrate 1p (1.0 mmol), chiral organoiodine 3d (10 mol%), mcpba (1.3 equiv) and TFE/CH 3 CN (4.0 ml) was added CF 3 CO 2 H (4.0 equiv). The resulting mixture was allowed to be stirred at room temperature for 8 h. Then, the mixture was filtered, washed with CH 3 CN (2 ml 2), the combined organic phase was removed in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/etoac = 3/1) to afford intermediate A as a white solid (81%, 234 mg). S3

4 III. Preparation of Substrate 1. 1 a. Preparation of 3-oxoglutaric anhydride 3-Oxoglutaric acid (100 g, 0.68 mol) was added by portions to a solution of acetic acid (150 ml) and acetic anhydride (100 ml) at 5 C and stirred below 10 C. The acid dissolved slowly and a pale yellow solid precipitated over 3 h. The product was filtered, washed with acetic acid (100 ml), and followed by methylbenzene (100 ml 3). The resultant white powder was dried at high vacuum to afford 76 g (86.7%) of the desired 3-oxoglutairc anhydride, which was used directly in the following step. b. Preparation of monoester 3-oxoglutarate To 3-oxoglutairc anhydride (2 g, 16 mmol) was add cold dry alcohol (12 ml). The mixture was stirred at room temperature for 2 h and the solvent was evaporated to give a brown liquid product with quantitative yield, which was used directly for the next step without further purification. c. General procedure for the preparation of ethyl 3-oxopentanioate monoamide derivatives Aniline derivatives (12.0 mmol), DMAP (1.0 mmol) and monoester 3-oxoglutarate (10.0 mmol) was mixed in CH 2 Cl 2 (20 ml) with an ice bath. Then DCC (12.0 mmol) was added by portions. After addition, the ice bath was removed and the reaction was maintained at room temperature for 12 hours. The mixture was filtered, washed with minimum amount of CH 2 Cl 2 for several times (10 ml 3). The combined organic phase was washed with 10% HCl solution and saturated brine, dried over Na 2 SO 4 and S4

5 evaporation of the solvent under reduced pressure and purification of the crude residue by flash column chromatography on silica gel (EA/PE) afforded the desired amides. IV. Preparation of the Optically Inactive Spirofurooxindoles 2 a. Optimization of the reaction conditions. a Entry Oxidant Additive (equiv) Solvent t ( o C) Yield (%) b 1 PIDA BF. 3 Et 2 O (0.1) DCE rt 25 2 PIDA none DCE PIFA none DCE rt 32 4 PIFA none DCE PIFA none C 2 H 5 O rt 0 c 6 PIFA none CH 3 CN rt 81 7 PIFA none HFIP rt 33 8 PIFA none CH 3 NO 2 rt 78 9 PIFA none TFE rt PIFA DBU (4) TFE rt 0 c 11 PIFA Et 3 N (4) TFE rt 0 c 12 PIFA Na 2 CO 3 (2) TFE rt 0 c 13 PIFA NaHCO 3 (4) TFE rt 81 a Reaction conditions: 1a (0.5 mmol) and oxidant (2.2 mmol), in solvent (5 ml). b Isolated yield. c Decomposition b. General procedure for the synthesis of the optically inactive spirofurooxindoles 2 To a solution of substrate 1 (0.5 mmol) in TFE (5 ml) was slowly added PIFA (2.2 equiv) with stirring. The resulting mixture was maintained at room temperature, and the process of the reaction was monitored by TLC. Upon completion, the reaction solvent was removed under vacuum and the residue was purified by silica gel S5

6 chromatography, using a mixture of PE/EA to afford the desired product 2. c. Investigation of a substrate of an ester a Entry Oxidant Solvent t ( o C) Yield (%) b 1 PIDA DCE rt 0 c 2 PIDA DCE c 3 PIDA DCE c 4 PIFA DCE rt 0 c 5 PIFA C 2 H 5 O rt 0 c 6 PIFA CH 3 CN rt 0 c 7 PIFA HFIP rt 0 c 8 PIFA TFE rt 0 c 9 PIFA TFE c 10 PIFA CH 3 NO 2 rt 0 c a Reaction conditions: 1q (0.5 mmol) and oxidant (2.2 mmol), in solvent (5 ml). b Isolated yield. c Decomposition V. Preparation of chiral iodobenzene (2R,2'R)-Diethyl 2,2'-(2-iodo-1,3-phenylene)bis(oxy)dipropanoate (3a): To a solution of 2-iodoresorcinol (2.36 g, 10.0 mmol), PPh 3 (6.56 g, 25.0 mmol) and ( )-lactic acid ethylester (2.80 ml, 25.0 mmol) in THF (50 ml) was added slowly S6

7 diisopropyl azodicarboxylate (DIAD, 1.9 M in toluene, 25.0 mmol, 13.2 ml) at 0 C. The reaction mixture was allowed to warm to room temperature. After stirring for 6 h, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: hexane EtOAc = 15:1) to give (3.93 g, 9.0 mmol) in 90% yield. Colorless oil; TLC, R f = 0.33 (hexane EtOAc = 4:1). (2R,2'R)-2,2'-(2-Iodo-1,3-phenylene)bis(oxy)dipropanoic acid (3b): To a solution of 3a (3.93 g, 9.0 mmol) in THF (25.0 ml) and MeOH (25.0 ml) was added 2N NaOH (25 ml) and stirred overnight at room temperature. The reaction mixture was cooled to 0 C, quenched with 1N HCl and extracted with EtOAc (30 ml 3). The organic layers were dried over anhydrous MgSO 4 and the solvents were removed in vacuo to give analytically pure 3b (3.42 g, 9.0 mmol) in >99% yield. White solid; TLC, R f = 0.15 (hexane EtOAc CHCl 3 = 1:2:1 with a few drops of AcOH). General procedure for preparation of 3c-j: To a solution of (2R,2'R)-2,2'- ((2-iodo-1,3-phenylene)bis(oxy))dipropanoic acid (0.87 g, 2.29 mmol) in CH 2 Cl 2 (10 ml) and DMF (1 drop) was added oxalyl chloride (1.57 ml, mmol) and the mixture was stirred overnight under N 2. The resulting mixture was concentrated under vacuum. The residue was dissolved in CH 2 Cl 2 (6 ml) at 0 C and amine derivative (4.17 mmol) was added. After 0.5 h, Et 3 N (1.16 ml, 8.34 mmol) was added. After stirring overnight, the reaction mixture was poured into aqueous HCl (1 M, 20 ml) and extracted with brine and CH 2 Cl 2 (10 ml 2). The organic layers were dried with MgSO 4, filtered and the solvent was removed under vacuum to give the product as a white solid. VI. Preparation of the Optically Active Spirofurooxindoles 2 To a reaction tube filled with ethyl 5-(methyl(phenyl)amino)-3,5-dioxopentanoate 1a (0.2 mmol), chiral organoiodine 3d (20 mol%), mcpba (2.5 equiv) and TFE/CH 3 CN (4.0 ml) was added CF 3 CO 2 H (4.0 equiv). The resulting mixture was allowed to be stirred at room temperature for 8 h. The mixture was filtered, washed with CH 3 CN (2 ml 2), the combined organic phase was removed in vacuo. The S7

8 residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/etoac = 3/1) to afford (R)-5-ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline] -2',3- dione 2a as a white solid. Ethyl 5-(methyl(phenyl)amino)-3,5-dioxopentanoate (1a) Following the general procedure, 1a was purified by silica gel chromatography (20% EA/PE). Yield: 71% (1.87 g), colorless oil. IR (KBr) 2934, 1740, 1649, 1594, 1469, 1384, 775, 702 cm -1. Mixture of enol and keto form: 1 H NMR (600 MHz, CDCl 3 ) δ (s, 0.28), (s, 0.01H), 7.43 (t, J = 6.3 Hz, 2H), 7.38 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 7.5 Hz, 2H), 5.01 (s, 0.04H), 4.82 (s, 0.34H), (m, 2H), 3.51 (s, 1H), 3.44 (s, 1H), 3.30 (d, J = 8.6 Hz, 3H), 3.06 (s, 0.8H), (m, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ , 172.4, 171.6, 171.4, 168.6, 168.4, 167.0, 166.3, 143.3, 143.0, 130.0, 129.9, 129.7, 128.4, 127.9, 127.3, 127.2, 91.8, 90.9, 61.4, 61.2, 60.2, 49.2, 48.9, 41.6, 40.5, 37.6, 37.3, 36.5, 14.2, HRMS (ESI) + calcd for C 14 H 17 NNaO 4 [M + Na + ] , found Ethyl 5-(ethyl(phenyl)amino)-3,5-dioxopentanoate (1b) Following the general procedure, 1b was purified by silica gel chromatography (20% EA/PE). Yield: 63% (1.75 g), colorless oil. IR (KBr) 2980, 1741, 1650, 1593, 1495, 1369, 771, 702 cm -1. Mixture of enol and keto form: 1 H NMR (600 MHz, CDCl 3 ) δ (s, 0.23H), (s, 0.02H), 7.44 (t, J = 7.1 Hz, 2H), 7.39 (d, J = 6.5 Hz, 1H), 7.18 (d, J = 7.4 Hz, 2H), 5.00 (s, 0.04H), 4.69 (s, 0.33H), (m, 2H), 3.77 (d, J = 6.9 Hz, 2H), 3.50 (s, 1H), 3.38 (s, 1H), 3.04 (s, 0.8H), S8

9 (m, 3H), 1.14 (t, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 197.3, 172.4, 171.8, 171.0, 168.6, 168.5, 167.0, 166.6, 165.8, 141.6, 141.4, 129.9, 129.8, 129.7, 128.6, 128.5, 128.3, 128.0, 91.8, 91.2, 61.3, 61.2, 49.3, 49.2, 44.2, 43.5, 41.6, 40.9, 14.1, , HRMS (ESI) calcd for C 15 H 19 NNaO 4 [M + Na + ] , found Ethyl 5-(isopropyl(phenyl)amino)-3,5-dioxopentanoate (1c) Following the general procedure, 1c was purified by silica gel chromatography (20% EA/PE). Yield: 56% (1.63 g), colorless oil. IR (KBr) 2979, 1742, 1645, 1590, 1494, 1317, 772, 705 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.31H), (s, 0.03H), (m, 3H), (m, 2H), 4.98 (dt, J = 13.5, 6.8 Hz, 1H), 4.46 (s, 0.31H), (m, 2H), 3.45 (s, 1.33H), 3.27 (s, 1.34H), 3.00 (s, 0.66H), 2.89 (s, 0.09H), (m, 3H), 1.07 (t, J = 6.2 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.4, 171.9, 171.0, 168.5, 168.4, 167.0, 166.5, 165.8, 137.9, 137.6, 130.5, 130.4, 130.2, 129.5, 129.4, 129.3, 128.8, 128.4, 91.8, 61.3, 61.1, 60.1, 49.9, 49.2, 46.4, 45.6, 41.5, 21.0, 20.9, 14.2, HRMS (ESI) + calcd for C 16 H 21 NNaO 4 [M + Na + ] , found Ethyl 5-(butyl(phenyl)amino)-3,5-dioxopentanoate (1d) Following the general procedure, 1d was purified by silica gel chromatography (20% EA/PE). Yield: 61% (1.86 g), colorless oil. IR (KBr) 2960, 1742, 1650, 1593, 1495, 1369, 774, 702 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, S9

10 CDCl 3 ) δ (s, 0.31H), (s, 0.02H), (m, 2H), (m, 1H), (m, 2H), 5.00 (s, 0.03H), 4.70 (s, 0.33H), (m, 2H), 3.72 (dd, J = 14.3, 6.7 Hz, 2H), 3.50 (s, 1.66H), 3.37 (s, 1.66H), 3.04 (s, 0.66H), 3.00 (s, 0.10H), (m, 2H), (m, 2H), (m, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.3, 171.2, 168.6, 168.5, 167.0, 166.0, 141.9, 141.6, 129.9, 129.8, 129.7, 128.4, 128.4, 128.2, 128.0, 91.8, 91.1, 61.3, 61.2, 60.1, 50.3, 49.3, 49.3, 49.2, 49.1, 48.4, 41.6, 40.9, 29.9, 29.7, 20.0, 20.0, 14.1, HRMS + (ESI) calcd for C 17 H 23 NNaO 4 [M + Na + ] , found Ethyl 5-(benzyl(phenyl)amino)-3,5-dioxopentanoate (1e) Following the general procedure, 1e was purified by silica gel chromatography (20% EA/PE). Yield: 67% (2.27 g), a light yellow solid, mp o C. IR (KBr) 2982, 1737, 1647, 1594, 1495, 1329, 763, 703 cm -1. Mixture of enol and keto form: 1 H NMR (600 MHz, CDCl 3 ) δ (s, 0.28H), (s, 0.05H), 7.32 (s, 3H), (m, 3H), 7.21 (d, J = 6.6 Hz, 2H), (m, 2H), 4.91 (d, J = 11.6 Hz, 2H), 4.76 (s, 0.33H), (m, 2H), 3.49 (s, 1.13H), 3.45 (s, 1H), 3.06 (s, 0.8H), (m, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 197.2, 171.3, 169.1, 168.5, 166.9, 166.4, 141.5, 141.5, 137.1, 136.8, 129.8, 129.6, 128.9, 128.8, 128.6, 128.6, 128.5, 128.4, 128.4, 128.1, 127.6, 127.5, 92.0, 91.1, 61.4, 61.3, 60.2, 53.4, 53.1, 52.3, 49.2, 49.1, 41.6, 40.8, 14.3, HRMS (ESI) calcd for C 20 H 21 NNaO + 4 [M + Na + ] , found Ethyl 5-(methyl(p-tolyl)amino)-3,5-dioxopentanoate (1f) S10

11 Following the general procedure, 1f was purified by silica gel chromatography (20% EA/PE). Yield: 73% (2.02 g), colorless oil. IR (KBr) 2981, 1742, 1651, 1514, 1466, 1327, 783, 722 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.21H), (s, 0.01H), 7.22 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 5.01 (s, 0.04H), 4.82 (s, 0.34H), (m, 2H), 3.51 (s, 1.11H), 3.43 (s, 1.17H), 3.27 (s, 3H), 3.05 (s, 0.77H), 2.38 (s, 3H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.3, 172.4, 171.8, 171.5, , 167.0, 166.4, 141.0, 140.7, 140.5, 138.4, 137.8, 130.6, 130.5, 130.3, 127.1, 126.9, 91.8, 90.9, 61.3, 61.2, 60.1, 49.2, 48.9, 41.5, 40.4, 37.6, 37.3, 36.5, 21.1, 14.2, HRMS (ESI) calcd for C 15 H 19 NNaO + 4 [M + Na + ] , found Ethyl 5-((4-methoxyphenyl)(methyl)amino)-3,5-dioxopentanoate (1g) Following the general procedure, 1g was purified by silica gel chromatography (20% EA/PE). Yield: 76% (2.23 g), colorless oil. IR (KBr) 2980, 1741, 1650, 1512, 1467, 1369, 840, 783 cm -1. Mixture of enol and keto form: 1 H NMR (600 MHz, CDCl 3 ) δ (s, 0.31H), (s, 0.08H), 7.12 (dd, J = 9.0, 3.0 Hz, 2H), 6.92 (dd, J = 8.9, 2.4 Hz, 2H), 5.01 (s, 0.03H), 4.80 (s, 0.32H), 4.13 (dt, J = 12.8, 6.6 Hz, 2H), 3.83 (d, J = 5.0 Hz, 3H), 3.51 (s, 1.22H), 3.42 (s, 1.20H), 3.26 (d, J = 8.8 Hz, 3H), 3.05 (s,.0.77h), 1.23 (dt, J = 20.9, 7.1 Hz, 3H). 13 C NMR (150MHz, CDCl 3 ) δ 197.3, 171.7, 168.5, 168.4, 167.0, 166.7, 159.3, 159.0, 136.1, 135.8, 128.4, 128.3, 115.1, 115.0, 114.9, 91.7, 90.9, 61.3, 61.2, 55.5, 49.2, 48.9, 41.6, 37.5, 36.6, HRMS (ESI) calcd for C 15 H 19 NNaO + 5 [M + Na + ] , found S11

12 Ethyl 5-(methyl(4-(trifluoromethoxy)phenyl)amino)-3,5-dioxopentanoate (1h) Following the general procedure, 1h was purified by silica gel chromatography (20% EA/PE). Yield: 53% (1.84 g), colorless oil. IR (KBr) 2985, 1742, 1659, 1507, 1370, 1260, 788, 740 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.40H), (s, 0.04H), (m, 4H), 5.00 (s, 0.05H), 4.81 (s, 0.37H), (m, 2H), 3.53 (s, 1.10H), 3.45 (s, 1.11H), 3.30 (d, J = 7.5 Hz, 3H), 3.09 (s, 0.70H), 3.07 (s, 0.16H), 1.41 (td, J = 7.1, 2.4 Hz, 0.26H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 174.2, 172.3, 171.4, 171.1, 169.2, 168.3, 166.9, (s), 164.1, 162.3, 148.7, 148.2, 141.8, 141.5, 128.9, 124.2, 122.4, 122.2, 121.6, 119.1, 116.5, 92.0, 90.5, 82.1, 77.7, 65.1, 64.9, 61.4, 61.2, 60.2, 49.1, 48.8, 41.5, 40.5, 37.6, 37.4, 36.5, 14.2, 14.1, HRMS (ESI) calcd for C 15 H 16 F 3 NNaO + 5 [M + Na + ] , found Ethyl 5-((4-fluorophenyl)(methyl)amino)-3,5-dioxopentanoate (1i) Following the general procedure, 1i was purified by silica gel chromatography (20% EA/PE). Yield: 57% (1.60 g), colorless oil. IR (KBr) 2983, 1741, 1651, 1510, 1469, 1370, 847, 727 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.32H), (s, 0.03H), 7.22 (tt, J = 11.4, 5.7 Hz, 2H), 7.12 (dt, J = 8.7, 2.6 Hz, 2H), 5.00 (s, 0.05H), 4.78 (s, 0.34H), (m, 2H), 3.52 (s, 1H), 3.43 (s, 1.12H), 3.28 (d, J = 5.8 Hz, 3H), 3.07 (s, 0.6H), 3.04 (s, 0.2H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 172.3, 171.5, 171.3, 168.9, 168.4, 167.2, 166.9, 166.3, 163.2, 163.0, 160.8, 160.5, 139.3, 139.0, 129.2, 129.1, 117.0, 116.8, 116.6, 93.1, 91.9, 90.7, 61.4, 61.2, 60.2, 49.1, 48.9, 41.5, 40.5, 38.9, 37.7, 37.5, S12

13 36.6, 14.2, HRMS (ESI) calcd for C 14 H 16 FNNaO 4 + [M + Na + ] , found Ethyl 5-((4-chlorophenyl)(methyl)amino)-3,5-dioxopentanoate (1j) Following the general procedure, 1j was purified by silica gel chromatography (20% EA/PE). Yield: 65% (1.93 g), colorless oil. IR (KBr) 2982, 1740, 1656, 1544, 1491, 1369, 841, 724 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.36H), (s, 0.04H), 7.41 (d, J = 8.3 Hz, 2H), (m, 2H), 5.01 (s, 0.05H), 4.80 (s, 0.36H), (m, 2H), 3.53 (s, 1H), 3.45 (s, 1H), 3.28 (d, J = 6.9 Hz, 3H)., 3.08 (s, 0.66H), 3.05 (s, 0.15H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 172.3, 171.4, 171.2, 169.1, 168.4, 166.9, 166.2, 141.8, 141.6, 134.3, 133.6, 130.2, 130.0, 128.7, 92.0, 90.7, 61.5, 61.3, 60.3, 49.2, 48.9, 42.0, 41.5, 40.5, 37.7, 37.4, 36.5, 14.2, HRMS (ESI) calcd for C 14 H ClNNaO + 4 [M + Na + ] , found Ethyl 5-((4-bromophenyl)(methyl)amino)-3,5-dioxopentanoate (1k) Following the general procedure, 1k was purified by silica gel chromatography (20% EA/PE). Yield: 70% (2.39 g), colorless oil. IR (KBr) 2982, 1740, 1565, 1587, 1475, 1369, 791, 698 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.43H), (s, 0.03H), 7.51 (t, J = 9.0 Hz, 1H), (m, 1H), (m, 1H), 7.18 (t, J = 6.5 Hz, 1H), 5.01 (s, 0.05H), 4.83 (s, 0.39H), (m, 2H), 3.54 (s, 1H), 3.45 (s, 1H), 3.28 (d, J = 6.7 Hz, 3H)., 3.10 (s, 1H), 1.24 (dt, J = 10.3, 7.1 Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ 197.0, 171.3, 169.3, 168.3, 166.9, 166.1, 144.5, 144.3, 131.6, 131.3, 131.0, 131.0, 130.6, 130.5, 126.2, S13

14 126.1, 123.2, 122.9, 92.0, 90.6, 61.5, 61.4, 60.3, 49.2, 48.8, 41.6, 37.4, 36.5, HRMS (ESI) calcd for C 14 H BrNNaO 4 + [M + Na + ] , found Ethyl 5-((3,4-dichlorophenyl)(methyl)amino)-3,5-dioxopentanoate (1l) Following the general procedure, 1l was purified by silica gel chromatography (20% EA/PE). Yield: 61% (2.02 g), colorless oil. IR (KBr) 2982, 1740, 1658, 1588, 1473, 1368, 711, 679 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.43H), (s, 0.03H), 7.51 (dd, J = 8.5, 2.8 Hz, 1H), (m, 1H), (m, 1H), 5.01 (s, 0.06H), 4.85 (s, 0.38H), 4.15 (qd, J = 7.1, 1.9 Hz, 2H), 3.54 (s, 1H), 3.47 (s, 1H), 3.28 (d, J = 7.7 Hz, 3H), 3.11 (s, 1H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 196.9, 172.3, 171.3, 170.8, 169.7, 168.2, 166.9, 166.0, 142.6, 142.4, 133.8, 133.5, 132.8, 131.6, 131.4, 129.4, 126.8, 92.1, 90.5, 61.5, 61.3, 60.3, 49.1, 48.8, 41.5, 37.4, 36.5, 14.2, HRMS (ESI) calcd for C 14 H Cl 2 NNaO + 4 [M + Na + ] , found Ethyl 5-(methyl(o-tolyl)amino)-3,5-dioxopentanoate (1m) Following the general procedure, 1m was purified by silica gel chromatography (20% EA/PE). Yield: 51% (1.41 g), colorless oil. IR (KBr) 2982, 1741, 1651, 1579, 1493, 1370, 733, 728 cm -1. Mixture of enol and keto form: 1 H NMR (600 MHz, CDCl 3 ) δ (s, 0.24H), (s, 0.02H), (m, 3H), (m, 1H), 4.98 (s, 0.04H), 4.61 (s, 0.38H), (m, 2H), 3.51 (s, 1H), (m, 1.22H), 3.22 (d, J = 7.1 Hz, 3H), 3.04 (s, 0.79H), 2.23 (d, J = 20.1 Hz, 3H), 1.21 (d, J = 27.4 Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ 197.1, 171.5, 168.8, 168.4, 167.0, 166.6, 141.7, 141.5, 135.8, 135.4, 131.7, 131.6, 131.4, 129.0, 128.6, 128.1, 128.1, S14

15 127.7, 127.5, 92.0, 90.5, 61.4, 61.2, 60.2, 49.3, 48.5, 41.5, 40.2, 36.2, 36.0, 35.2, 17.4, 17.3, 14.2, HRMS (ESI) calcd for C 15 H 19 NNaO 4 + [M + Na + ] , found Methyl 5-(methyl(phenyl)amino)-3,5-dioxopentanoate (1n) Following the general procedure, 1n was purified by silica gel chromatography (20% EA/PE). Yield: 75% (1.87 g), colorless oil. IR (KBr) 2953, 1745, 1649, 1593, 1496, 1385, 755, 702 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.31H), (s, 0.01H), (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 2H), 5.03 (s, 0.04H), 4.82 (s, 0.36H), (m, 3H), 3.53 (s, 1.12H), 3.43 (s, 1.14H), 3.30 (d, J = 6.9 Hz, 3H), 3.07 (s, 0.78H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 171.7, 171.4, 168.9, 168.3, 167.4, 167.1, 166.3, 143.3, 143.0, 130.0, 129.9, 129.8, 128.4, 128.3, 127.9, 127.3, 127.2, 91.5, 91.1, 52.3, 52.3, 51.3, 48.9, 41.3, 40.5, 37.6, 37.3, HRMS (ESI) calcd for C 13 H 15 NNaO + 4 [M + Na + ] , found Isopropyl 5-(methyl(phenyl)amino)-3,5-dioxopentanoate (1o) Following the general procedure, 1o was purified by silica gel chromatography (20% EA/PE). Yield: 55% (1.52 g), colorless oil. IR (KBr) 2982, 1735, 1651, 1593, 1496, 1376, 774, 701 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.22H), (s, 0.04H), 7.43 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 6.8 Hz, 1H), (m, 2H), (m, 1H), 4.81 (s, 0.31), 3.47 (s, 1H), 3.43 (s, 1.10H), 3.30 (s, 3H), 3.05 (s, 0.77H), 1.22 (dt, J = 17.0, 8.6 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.3, 172.0, 171.5, 171.4, 168.9, 167.9, 167.2, 166.5, 166.3, 143.3, S15

16 143.1, 130.0, 129.9, 129.7, 128.4, 127.8, 127.3, 127.2, 92.2, 90.6, 69.0, 68.7, 67.6, 49.5, 48.9, 41.8, 40.4, 37.3, 36.5, 21.9, HRMS (ESI) calcd for C 15 H 19 NNaO 4 + [M + Na + ] , found Butyl 5-(methyl(phenyl)amino)-3,5-dioxopentanoate (1p) Following the general procedure, 1p was purified by silica gel chromatography (20% EA/PE). Yield: 58% (1.52 g), colorless oil. IR (KBr) 2961, 1741, 1650, 1593, 1496, 1383, 774, 701 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.29H), (s, 0.01H), (m, 2H), 7.37 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 5.02 (s, 0.05H), 4.82 (s, 0.33H), (m, 2H), 3.51 (s, 1.14H), 3.43 (s, 1.15H), 3.30 (d, J = 6.6 Hz, 3H)., 3.06 (s, 0.82H), (m, 2H), (m, 2H), 0.92 (td, J = 7.4, 5.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 197.2, 172.5, 171.6, 171.4, 168.6, 168.5, 167.0, 166.3, 143.3, 143.0, 130.0, 129.9, 129.7, 128.4, 127.8, 127.3, 127.2, 91.8, 90.9, 65.2, 65.1, 64.0, 49.2, 48.9, 41.6, 40.5, 37.6, 37.3, 36.5, 30.6, 30.4, 19.1, 19.0, HRMS (ESI) calcd for + C 16 H 21 NNaO 4 [M+Na + ] , found Ethyl 5-phenyl 3-oxopentanedioate (1q) Following the general procedure, 1q was purified by silica gel chromatography (20% EA/PE). Yield: 51% (1.27 g), colorless oil. IR (KBr) 2984, 1743, 1661, 1593, 1492, 1369, 753, 691 cm -1. Mixture of enol and keto form: 1 H NMR (400 MHz, CDCl 3 ) δ (s, 0.10H), (s, 0.14H), 7.39 (t, J = 7.3 Hz, 2H), (m, 1H), 7.12 (dt, J = 8.7, 1.6 Hz, 2H), 5.40 (s, 0.16H), 5.23 (s, 0.11H) (m, 2H), 3.86 (d, J = 1.2 Hz, 1.47H), 3.67 (s, J = 1.1 Hz, 1.55H), 3.60 (d, J = 0.9 Hz, 0.24H), 3.46 (s, S16

17 0.23H), 3.31 (s, 0.30H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 195.1, 172.3, 171.9, 169.2, 167.8, 166.7, 165.5, 150.5, 150.0, 129.6, 129.5, 126.3, 126.2, 121.6, 121.4, 115.3, 92.4, 91.6, 61.8, 61.7, 60.5, 49.1, 49.0, 48.9, 41.2, 41.0, HRMS (ESI) calcd for C 13 H 14 NaO 5 [M+Na + ] , found (2S,2'S)-Dimethyl1,1'-((2R,2'R)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))bis(propano yl))bis(pyrrolidine-2-carboxylate) (3d) Following the general procedure, 3d was purified by silica gel chromatography (PE/EA = 3/1 to 1/1). Yield: 85% (1.17 g), white solid, mp o C. 4 IR (KBr) 2983, 2956, 2892, 1743, 1655, 1462, 1421, 1254, 1141, 1096, 775 cm H NMR (400 MHz, CDCl 3 ) δ 7.18 (td, J = 8.3, 5.7 Hz, 1H), 6.48 (d, J = 8.3 Hz, 2H), 4.82 (q, J = 6.8 Hz, 2H), 4.46 (dd, J = 8.0, 3.1 Hz, 2H), 3.91 (td, J = 6.9, 3.6 Hz, 2H), 3.73 (s, 6H), 3.48 (dt, J = 10.5, 7.8 Hz, 2H), 3.31 (s, 1H), (m, 8H), 1.72 (dd, J = 6.8, 3.7 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 170.0, 157.5, 130.4, 106.2, , 59.6, 52.2, 46.9, 28.1, 25.2, HRMS (ESI) calcd for C 24 H 31 IN 2 NaO 8 [M + Na + ] , found [α] 25 D = (c = 0.54, CHCl 3 ). (R)-N-((R)-1,1-Dioxidotetrahydrothiophen-3-yl)-2-(3-(((R)-1-(((S)-1,1-dioxidotetr ahydrothiophen-3-yl)amino)-1-oxopropan-2-yl)oxy)-2-iodophenoxy) propanamide (3e) Following the general procedure, 3e was purified by silica gel chromatography (PE/EA = 3/1 to 1/1). Yield: 81% (1.14 g), white solid, mp o C. IR (KBr) 3378, 2986, 2937, 1663, 1585, 1553, 1459, 1305, 1250, 1116, 767 cm H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 7.1 Hz, 2H), (m, 1H), 6.52 (d, J = 8.3 S17

18 Hz, 2H), (m, 4H), 3.50 (dd, J = 13.6, 7.5 Hz, 2H), 3.16 (dtd, J = 26.3, 13.5, 6.3 Hz, 6H), 2.57 (td, J = 13.5, 6.7 Hz, 2H), 2.27 (td, J = 14.6, 7.5 Hz, 2H), 1.64 (d, J = 6.6 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 171.0, 156.7, 130.6, 107.1, , 75.8, 55.9, 50.3, 46.0, 29.3, HRMS (ESI) calcd for C 20 H 28 IN 2 O 8 S 2 [M + H + ] , found [α] 25 D = (c = 0.14, CHCl 3 ). (2R,2'R)-2,2'-((2-Iodo-1,3-phenylene)bis(oxy))bis(N,N-diisopropylpropanamide) (3 h) Following the general procedure, 3h was purified by silica gel chromatography (PE/EA = 3/1 to 1/1). Yield: 77% (962 mg), white solid, mp o C. 5 IR (KBr) 2967, 2936, 1743, 1643, 1623, 1585, 1460, 1376, 1345, 1237, 1106, 770 cm H NMR (400 MHz, CDCl 3 ) δ 7.14 (t, J = 8.0 Hz, 1H), 6.53 (d, J = 8.2 Hz, 2H), 4.85 (q, J = 6.5 Hz, 2H), 4.55 (dt, J = 12.5, 6.1 Hz, 2H), 3.31 (dt, J = 13.1, 6.4 Hz, 2H), 1.68 (d, J = 6.0 Hz, 6H), 1.42 (d, J = 6.6 Hz, 6H), 1.30 (d, J = 6.6 Hz, 6H), 1.20 (d, J = 6.3 Hz, 6H), 0.91 (t, J = 5.7 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 169.5, 157.6, 129.9, 106.1, 106.0, 78.5, 77.9, 47.6, 46.5, 20.9, 20.6, 20.6, 19.9, HRMS (ESI) + calcd for C 24 H 40 IN 2 O 4 [M+H + ] , found [α] 25 D = (c = 0.14, CHCl 3 ). (2R,2'R)-2,2'-((2-Iodo-1,3-phenylene)bis(oxy))bis(N,N-diallylpropanamide) (3i) Following the general procedure, 3h was purified by silica gel chromatography (PE/EA = 3/1 to 1/1). Yield: 82% (1.01 g), white solid, mp o C. IR (KBr) 3080, 2983, 2945, 2921, 1743, 1658, 1639, 1588, 1461, 1379, 1365, 1256, 1135, 858, 781 cm H NMR (400 MHz, CDCl 3 ) δ 7.16 (t, J = 8.3 Hz, 1H), 6.51 (d, J = 8.3 Hz, S18

19 2H), (m, 4H), (m, 10H), (m, 4H), 3.95 (qd, J = 15.3, 5.7 Hz, 4H), 1.69 (d, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 170.4, 157.7, 133.1, 132.3, 130.0, 117.7, 117.3, 106.8, 79.8, 76.0, 48.7, 47.7, HRMS + (ESI) calcd for C 24 H 32 IN 2 O 4 [M + H + ] , found [α] 25 D = (c = 0.28, CHCl 3 ). (2R,2'R)-2,2'-((2-Iodo-1,3-phenylene)bis(oxy))bis(1-(3,4-dihydroisoquinolin-2(1 H)-yl)propan-1-one) (3j) Following the general procedure, 3j was purified by silica gel chromatography (PE/EA = 3/1 to 1/1). Yield: 72% (969 mg), white solid, mp o C. IR (KBr) 2985, 2933, 1657, 1585, 1460, 1373, 1283, 1251, 1136, 1095, 751 cm H NMR (600 MHz, CDCl 3 ) δ (m, 9H), 6.48 (dd, J = 18.7, 8.5 Hz, 2H), (m, 3H), 4.78 (d, J = 17.5 Hz, 1H), 4.62 (dd, J = 16.8, 9.8 Hz, 2H), (m, 2H), (m, 2H), (m, 3H), (m, 1H), (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 169.5, 157.5, 157.3, 134.5, 133.9, 132.7, 132.6, 130.6, 130.5, 128.8, 128.4, 126.9, 126.6, 126.5, 126.5, 126.3, 126.1, 106.2, 106.1, 78.5, 47.0, 45.1, 42.7, 41.1, 40.3, 29.7, 28.2, 18.1, HRMS (ESI) + calcd for C 30 H 32 IN 2 O 4 [M + H + ] , found [α] 25 D = (c = 0.22, CHCl 3 ). (R)-5-Ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2a) Following the general procedure, 2a was purified by silica gel chromatography S19

20 (30% EA/PE). Yield: 63% (33 mg), white solid, mp o C. IR (KBr) 3112, 2933, 1735, 1702, 1583, 1352, 1002, 879, 771 cm H NMR (400 MHz, CDCl 3 ) δ 7.41 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.96 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.24 (s, 3H), 1.52 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 192.6, 186.4, 168.8, 145.3, 131.5, 124.1, 123.5, , 109.2, 89.2, 79.9, 68.9, 26.9, HRMS (ESI) calcd for C 14 H 13 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.12, CHCl 3 ). Enantiomeric excess: 87%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-1'-ethyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2b) Following the general procedure, 2b was purified by silica gel chromatograohy (30% EA/PE). Yield: 71% (39 mg), white solid, mp o C. IR (KBr) 3108, 2986, 1731, 1698, 1580, 1347, 1010, 881, 766 cm H NMR (600 MHz, CDCl 3 ) δ 7.39 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 4.95 (s, 1H), 4.41 (dd, J = 13.1, 6.3 Hz, 2H), 3.80 (td, J = 13.7, 6.9 Hz, 1H), 3.73 (td, J = 13.6, 6.7 Hz, 1H), 1.52 (t, J = 6.3 Hz, 3H), 1.30 (t, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 192.6, 186.4, 168.4, 144.4, 131.4, 124.3, 123.3, 123.0, , 89.2, 79.8, 68.9, 35.5, 14.3, HRMS (ESI) calcd for C 15 H 15 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.15, CHCl 3 ). Enantiomeric excess: 87%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was determined by X-ray crystallography analysis. S20

21 (R)-5-Ethoxy-1'-isopropyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (1c) Following the general procedure, 2c was purified by silica gel chromatography (30% EA/PE). Yield: 65% (37 mg), white solid, mp o C. IR (KBr) 3087, 2961, 1732, 1708, 1582, 1344, 1030, 884, 753 cm H NMR (400 MHz, CDCl 3 ) δ 7.36 (td, J = 7.9, 1.1 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.05 (dd, J = 14.6, 7.7 Hz, 2H), 4.94 (s, 1H), 4.51 (dt, J = 14.0, 7.0 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.51 (dd, J = 9.5, 3.9 Hz, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 192.6, 186.4, 168.4, 144.2, 131.2, 124.4, 123.2, 122.9, 110.6, 89.3, 79.7, 68.9, 45.1, 19.5, 19.1, HRMS + (ESI) calcd for C 16 H 17 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.15, CHCl 3 ). Enantiomeric excess: 82%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-1'-Butyl-5-ethoxy-3H-spiro[furan-2,3'-indoline]-2',3-dione (1d) Following the general procedure, 2d was purified by silica gel chromatography (30% EA/PE). Yield: 57% (34 mg), white solid, mp o C. IR (KBr) 3115, 2960, 1732, 1698, 1579, 1348, 1039, 885, 766 cm H NMR (400 MHz, CDCl 3 ) δ 7.38 (td, J = 7.8, 1.1 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.95 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.71 (td, J = 7.4, 2.2 Hz, 2H), 1.67 (ddd, J = 10.4, 7.0, 3.8 Hz, 2H), 1.52 (t, J = 7.1 Hz, 3H), 1.41 (dd, J = 14.8, S21

22 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 192.7, 186.4, 168.7, 144.8, 131.4, 124.3, 123.2, 122.9, 109.5, 89.2, 79.8, 68.9, 40.4, 29.3, 20.0, , HRMS (ESI) calcd for C 17 H 19 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.11, CHCl 3 ). Enantiomeric excess: 86%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-1'-Benzyl-5-ethoxy-3H-spiro[furan-2,3'-indoline]-2',3-dione (2e) Following the general procedure, 2e was purified by silica gel chromatograohy (30% EA/PE). Yield: 77% (52 mg), white solid, mp o C. IR (KBr) 3117, 2927, 1743, 1579, 1488, 1345, 1106, 882, 751 cm H NMR (600 MHz, CDCl 3 ) δ 7.33 (d, J = 3.5 Hz, 4H), 7.26 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.98 (t, J = 7.9 Hz, 2H), 4.86 (d, J = 15.9 Hz, 1H), 4.42 (q, J = 6.8 Hz, 2H), 1.52 (t, J = 6.9 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 192.6, 186.5, 169.0, 144.3, 134.6, 131.4, 129.0, 127.8, 127.1, 124.2, 123.5, 122.8, , 89.3, 79.7, 69.1, 44.3, HRMS (ESI) calcd for C 20 H 17 NNaO 4 [M+Na + ] , found [α] 25 D = (c = 0.21, CHCl 3 ). Enantiomeric excess: 90%, determined by HPLC (Chiracel-OJ, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-1',5'-dimethyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2f) S22

23 Following the general procedure, 2e was purified by silica gel chromatography (30% EA/PE). Yield: 58% (32 mg), white solid, mp o C. IR (KBr) 3120, 2960, 1735, 1707, 1586, 1379, 1003, 888, 767 cm H NMR (600 MHz, CDCl 3 ) δ 7.20 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.78 (d, J = 7.9 Hz, 1H), 4.95 (s, 1H), 4.41 (q, J = 6.9 Hz, 2H), 3.21 (s, 3H), 2.31 (s, 3H), 1.52 (t, J = 7.0 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 192.8, 186.4, 168.7, 142.9, 133.2, 131.8, 124.9, 122.7, 109.0, 89.3, , 68.9, 26.9, 21.0, HRMS (ESI) calcd for C 15 H 15 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.20, CHCl 3 ). Enantiomeric excess: 86%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-5'-methoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2g) Following the general procedure, 2g was purified by silica gel chromatography (30% EA/PE). Yield: 55% (32 mg), white solid, mp o C. IR (KBr) 3117, 2944, 1730, 1704, 1584, 1496, 1344, 1029, 881, 804, 765 cm H NMR (600 MHz, CDCl 3 ) δ 6.92 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.9 Hz, 2H), 4.96 (s, 1H), 4.41 (dd, J = 12.8, 6.1 Hz, 2H), 3.76 (s, 3H), 3.20 (s, 3H), 1.51 (t, J = 6.5 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 192.6, 186.5, 168.5, 156.5, 138.5, 123.7, , 111.0, 109.8, , 79.8, 69.0, 55.9, 27.0, HRMS (ESI) calcd for C 15 H 15 NNaO 5 [M + Na + ] S23

24 , found [α] 25 D = (c = 0.27, CHCl 3 ). Enantiomeric excess: 90%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-1'-methyl-5'-(trifluoromethoxy)-3H-spiro[furan-2,3'-indoline]-2',3 -dione (2h) Following the general procedure, 2h was purified by silica gel chromatography (30% EA/PE). Yield: 62% (43 mg), white solid, mp o C. IR (KBr) 3117, 2990, 1740, 1716, 1586, 1472, 1348, 1104, 881, 861, 774 cm H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.96 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.24 (s, 3H), 1.54 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 191.6, 186.5, 168.6, (d, J C-F = 2.0 Hz), 143.9, 124.6, (s), (d, J C-F = Hz), (d, J C-F = Hz), 118.1, (d, J C-F = Hz), 109.9, 88.6, 79.6, 69.3, 27.1, HRMS (ESI) calcd for + C 15 H 12 F 3 NNaO 5 [M + Na + ] , found [α] 25 D = (c = 0.18, CHCl 3 ). Enantiomeric excess: 89%, determined by HPLC (Chiracel-OD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (minor), t R = min (major). The absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-5'-fluoro-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2i) S24

25 Following the general procedure, 2i was purified by silica gel chromatography (30% EA/PE). Yield: 74% (41 mg), white solid, mp o C. IR (KBr) 3122, 2949, 1733, 1699, 1579, 1494, 1349, 1005, 878, 765 cm H NMR (600 MHz, CDCl 3 ) δ 7.12 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.95 (s, 1H), 4.42 (d, J = 6.6 Hz, 2H), 3.22 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 191.9, 186.5, 168.5, (d, J C-F = Hz), 141.3, (d, J C-F = 8.4 Hz), (d, J C-F = 23.5 Hz), (d, J C-F = 25.5 Hz), (d, + J C-F = 8.0 Hz), 88.8, 79.7, 69.2, 27.0, HRMS (ESI) calcd for C 14 H 12 FNNaO 4 [M + Na + ] , found [α] D 25 = (c = 0.23, CHCl 3 ). Enantiomeric excess: 89%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5'-Chloro-5-ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2j) Following the general procedure, 2j was purified by silica gel chromatography (30% EA/PE). Yield: 67% (39 mg), white solid, mp o C. IR (KBr) 3129, 2934, 1739, 1712, 1585, 1489, 1378, 1044, 884, 731 cm H NMR (600 MHz, CDCl 3 ) δ 7.37 (d, J = 6.9 Hz, 1H), 7.19 (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.96 (s, 1H), (m, 2H), 3.22 (d, J = 6.4 Hz, 3H), 1.52 (t, J = 6.4 Hz, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 191.9, 186.5, 168.4, 143.8, 131.4, 128.8, 124.6, 124.2, S25

26 110.3, 88.6, 79.7, 69.3, 27.0, HRMS (ESI) calcd for C 14 H ClNNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.14, CHCl 3 ). Enantiomeric excess: 88%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5'-Bromo-5-ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2k) Following the general procedure, 2k was purified by silica gel chromatography (30% EA/PE). Yield: 69% (46 mg), white solid, mp o C. IR (KBr) 3127, 2987, 1740, 1711, 1585, 1487, 1377, 1043, 885, 738 cm H NMR (600 MHz, CDCl 3 ) δ 7.53 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 6.7 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 4.96 (d, J = 7.8 Hz, 1H), (m, 2H), 3.22 (d, J = 7.9 Hz, 3H), 1.54 (d, J = 6.9 Hz, 3H). 13 C NMR (150MHz, CDCl 3 ) δ 191.8, 186.5, 168.3, 144.3, 134.2, 127.3, 124.6, 116.0, 110.7, 88.5, 79.7, 69.2, 27.0, HRMS (ESI) calcd for C 14 H BrNNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.13, CHCl 3 ). Enantiomeric excess: 90%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-4',5'-Dichloro-5-ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2l) and (R)-5',6'-dichloro-5-ethoxy-1'-methyl-3H-spiro[furan-2,3'-indoline] -2',3- dione (2l ) S26

27 Following the general procedure, 2l and 2l were isolated and purified as a mixture by silica gel chromatography (30% EA/PE). Yield: 58% (38 mg), white solid, mp o C. IR (KBr) 3097, 2987, 1741, 1703, 1580, 1460, 1347, 1043, 875, 747 cm H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 8.4 Hz, 1.21H), 7.28 (d, J = 1.1 Hz, 1.20H), 7.00 (s, 0.96H), 6.77 (d, J = 8.4 Hz, 1.21H), 5.08 (s, 1.19H), 4.96 (s, 1H), 4.43 (p, J = 7.2 Hz, 4.48H), 3.21 (s, 6.63H), 1.53 (td, J = 7.1, 2.0 Hz, 6.62H). 13 C NMR (100MHz, CDCl 3 ) δ 191.6, 190.9, 186.5, 186.1, 168.2, 167.8, 145.3, 144.6, 135.6, 132.9, 130.4, 127.5, 127.1, 126.0, 122.3, 121.8, 111.4, 108.3, 88.4, 88.0, 81.2, 79.7, 69.5, 69.2, 27.1, 14.3, HRMS (ESI) calcd for C 14 H C l2 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.19, CHCl 3 ). Enantiomeric excess: 2l: 91%, 2l : 86%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 90/10, flow rate 1.0 ml/min, T = 25 o C, 254 nm): 2l: t R = min (minor), t R = min (major). 2l : t R = min (minor), t R = min (major).the absolute configuration was tentatively assigned by analogy. (R)-5-Ethoxy-1',7'-dimethyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2m) Following the general procedure, 2m were purified by silica gel chromatography (30% EA/PE). Yield: 46% (25 mg), white solid, mp o C. IR (KBr) 3095, 2933, 1730, 1699, 1576, 1456, 1379, 1076, 860, 749 cm H NMR (600 MHz, CDCl 3 ) δ 7.12 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 4.94 (s, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.49 (s, 3H), 2.56 (s, 3H), 1.51 (t, J = 7.0 Hz, S27

28 3H). 13 C NMR (150MHz, CDCl 3 ) δ 192.8, 186.4, 169.5, 142.9, 135.3, 123.4, 123.3, 122.0, 121.0, 89.1, 79.8, 68.9, 30.2, 18.9, HRMS (ESI) calcd for + C 15 H 15 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.12, CHCl 3 ). Enantiomeric excess: 74%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Methoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2n) Following the general procedure, 2n were purified by silica gel chromatography (30% EA/PE). Yield: 51% (25 mg), white solid, mp o C. IR (KBr) 3122, 2956, 1731, 1702, 1586, 1494, 1363, 987, 928, 767 cm H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.99 (s, 1H), 4.11 (d, J = 0.9 Hz, 3H), 3.23 (d, J = 0.8 Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ 192.5, 187.3, 168.7, 145.3, 131.6, 124.2, 123.5, 122.6, , 89.5, 79.7, 58.9, HRMS (ESI) calcd for C 13 H 11 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.13, CHCl 3 ). Enantiomeric excess: 88%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Isopropoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2o) S28

29 Following the general procedure, 2o were purified by silica gel chromatography (30% EA/PE). Yield: 55% (30 mg), white solid, mp o C. IR (KBr) 3098, 2941, 1745, 1693, 1566, 1490, 1346, 1089, 976, 906, 800 cm H NMR (400 MHz, CDCl 3 ) δ 7.40 (td, J = 7.8, 1.1 Hz, 1H), (m, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.93 (s, 1H), 4.89 (dt, J = 12.3, 6.2 Hz, 1H), 3.23 (s, 3H), 1.50 (d, J = 2.7 Hz, 3H), 1.49 (d, J = 2.7 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 192.6, 185.7, 168.9, 145.3, 131.5, 124.1, 123.5, 122.9, 109.2, 89.0, 80.3, 77.9, 26.9, , HRMS (ESI) calcd for C 15 H 15 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.45, CHCl 3 ). Enantiomeric excess: 89%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. (R)-5-Butoxy-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',3-dione (2p) Following the general procedure, 2p were purified by silica gel chromatography (30% EA/PE). Yield: 59% (34 mg), white solid, mp o C. IR (KBr) 3130, 2946, 1730, 1698, 1575, 1492, 1354, 1044, 847, 778, 769 cm H NMR (400 MHz, CDCl 3 ) δ 7.41 (dd, J = 11.3, 4.3 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.95 (s, 1H), 4.34 (t, J = 6.5 Hz, 2H), 3.23 (s, 3H), (m, 2H), (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR S29

30 (100MHz, CDCl 3 ) δ 192.6, 186.6, 168.8, 145.3, 131.5, 124.1, 123.5, 122.8, 109.2, , 79.8, 72.7, 30.6, 26.9, 18.8, HRMS (ESI) calcd for C 16 H 17 NNaO 4 [M + Na + ] , found [α] 25 D = (c = 0.17, CHCl 3 ). Enantiomeric excess: 88%, determined by HPLC (Chiracel-AD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min (major), t R = min (minor). The absolute configuration was tentatively assigned by analogy. 5-Butoxy-N-methyl-3-oxo-N-phenyl-2,3-dihydrofuran-2-carboxamide (A) A were purified by silica gel chromatography (30% EA/PE). Yield: 81% (234 mg), white solid, mp o C. IR (KBr) 2966, 2876, 1697, 1665, 1601, 1471, 1392, 981, 701 cm H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 7.7 Hz, 4H), 7.39 (d, J = 8.6 Hz, 1H), 5.17 (s, 1H), 4.76 (s, 1H), 4.20 (qd, J = 7.8, 3.3 Hz, 2H), 3.36 (s, 3H), (m, 2H), 1.45 (dd, J = 15.1, 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 193.9, 186.4, 163.0, 142.0, 130.0, 128.6, 127.7, 80.1, 80.0, 72.3, , 30.5, 18.7, HRMS (ESI) calcd for C 16 H 19 NNaO 4 [M + Na + ] , found [α] 25 D = 0 (c = 0.23, CHCl 3 ). Enantiomeric excess: < 3%, determined by HPLC (Chiracel-OD, hexane / isopropanol = 80/20, flow rate 1.0 ml/min, T = 25 o C, 254 nm): t R = min, t R = min. S30

31 VII. References 1. Li, W.; Ma, X.; Fan, W.; Tao, X.; Li, X.; Xie, Z.; Zhang, Z. Org. Lett. 2011, 13, Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; MinamitsuJi, Y.; FuJioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, Wu, H.; He, Y.-P.; Xu, L.; Zhang, D.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2014, 53, Alhalib, A.; Kamouka, S.; Moran, W. J. Org. Lett. 2015, 17, VIII. 1 H-NMR, 13 C-NMR Spectra and HPLC Data S31

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115 2c Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S115

116 2d Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S116

117 2d Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S117

118 2e Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S118

119 2e Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S119

120 2f Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S120

121 2f Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S121

122 2g Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S122

123 2g Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S123

124 2h Peak RetTime Type Width Area Height Area # [min] [min] mau s [mau] % BMB BMB S124